Rift, who was a postal worker who lived simultaneously in the DC Universe and the Dakotaverse. When he became Rift, he treated both universes as playthings.
Dr. Hank Henshaw was basically a gag Expy of Dr. Reed Richards in a forgettable Superman comic in which a group of scientists become Fantastic Four Expies - but don't survive the radiation. Well, Henshaw survives, and becomes the Cyborg Superman, one of Superman's most powerful enemies.
Also from Superman, the monster Doomsday, who killedSuperman. It is eventually revealed that he was created through forced evolution on a random, harmless, adorable baby, turning it into a superstrong immortal killing machine.
Victor von Doom was the son of a Romani couple, though they were related to deposed former royalty. Things went awry when his mother sold her soul to the Devil and died when he was young, and he was raised by his father and a group of Roma. But the local barony demanded his father to use his intelligence to cure his dying wife's incurable disease. The fact his father wasn't able to save her, caused his father to go on the lam with Victor, and severe frostbite cost him his life. From that point onward, Victor von Doom used his intelligence to get a leg up in life, and when someone proved just as smart as he was ... he became Doctor Doom. Then he breaks the multiverse as Rabum Alal.
John Dee, aka Doctor Destiny, was a minor JLA villain who washed up and got locked away for years... until gaining control of the Materioptikon and becoming a global threat overnight, leading to a showdown with the Lord of Dreams himself.
...Which was inspired by what Alan Moore did in his Swamp Thing run with the Floronic Man, who realizes that with his control over the growth of plants, he can choke the world any time he wants.
Dr. Light. Turns out his harmless joke status was caused by an accidental magic lobotomy, and that his original personality was a lot morethreatening and now that he's beaten the effects he's a lot more dangerous. Creepiest bit, as brought on by way of retcon, is that for the years in between the League's been letting teenagers fight him without letting on how depraved he really is. His preference for rape has been so Flanderized to the point that many readers have begun to refer to him as 'Dr. Rape'.
Sinestro was just another inhabitant of his home planet when he was chosen to join the Green Lantern Corps. Rising as one of their greatest members, his obsession with order made him become absolute dictator of his home world. When he was exposed, he was cast out, forging a yellow ring to fight the other Lanterns, setting up Hal Jordan to destroy the Corps and eventually forging his own Yellow Lanterns to spread fear across the universe. And he still insists he's in the right for it all.
The Joker. Whether he was in fact a failing stand-up comedian or a two-bit criminal in the beginning, his One Bad Day turned him from Joe Blue Collar Average into a horrific monstrosity that frightens other villains. Particularly interesting in that he never gained any actual superpowers (other than an incredible resistance or immunity to poisons and toxins), instead deciding it'd be really funny if he concentrated all his efforts to racking up a bodycount that'd make an Evil Overlord blush. In fact, when counting only single, personal acts (not city-destroying, etc.) it's without question the highest body count in the DCU.
In a Justice League comic, Batman briefly becomes a New God by sitting on Metron's chair of omniscience. He almost immediately tries to learn the Joker's true name, merely saying "That's impossible!" when given an un-shown answer. Whether this means he didn't receive the name or received a name he didn't expect is currently up for interpretation.
Killer Moth was incompetent and weak. Then he made a Deal with the Devil to become "feared," and Charaxes, a man-eating Human/Moth hybrid, was created.
Mr. Freeze was once a cryogenics scientist who just wanted to cure his wife's fatal disease. One nasty accident later and he becomes a vengeful, emotionless supervillain.
The current version of Mr Freeze has been changed into always being a monster. He was sickly fascinated with cold since a child, killed his own mother, and the Nora he obsesses about is not related to him in any way.
The Penguin was little more than an unpopular child who was teased by other kids because of his appearance. When his mother died, her long illness costing him so much that the bank foreclosed on the family business, he turned to crime, only to be mocked by criminals too. This caused him to find some backbone that he never realized he had, stand up for himself by taking over a criminal gang by force, and eventually become one of Batman's greatest enemies.
The Scarecrow started out as a lanky, bullied bookworm. Wanting to turn the tables, he began a lifelong study of the psychology of fear. Later on, he began experimenting with the physiology of fear, becoming a maker of literal Nightmare Fuel.
For a while, people thought that Scarecrow wasn't much of a threat without his Fear Gas. Then he went out on a killing spree sending the city into the a state of panic causing some of the villains in Arkham to beg Batman not to bring Scarecrow back to the asylum.
This entire trope is essentially the synopsis of Batman Eternal, where a group of low tier, forgettable villains bring Gotham to its knees with the entire plan hinging on the theory that they're so low on Batman's food chain he wouldn't even be able to figure out who could commit a plan of its sheer scale without mistakenly targeting his A-class villains such as Ra's al Ghul or Riddler...and they were right.
Batman himself is a rare heroic version of this Trope. One night, a family out on the town takes a wrong turn down an alley. The parents are murdered by a mugger, leaving an eight-year-old boy orphaned and traumatized. It was the kind of random street crime that happens every day in Gotham City. It could have happened to anyone. Except that eight-year-old boy resolved to rise above his trauma, to avenge his parents, and to ensure that something like this never happened to anyone else ever again. After ten or fifteen years of training his mind and body to their peak performances, using his extensive family fortune to design and build custom crimefighting equipment, and using his family name and business contacts to develop a global network of assistants and allies, Bruce Wayne turns himself into the finest deductive mind in the DCU...and the greatest nightmare Gotham City criminals will ever know.
IDW's Transformers comic, Megatron Origin details the origins of... Megatron. The evil warlord that has terrorized the Galaxy for countless eons... was once a miner earning dirt pay who got laid off, didn't take it lying down, and was arrested for killing a security officer in self-defense. Later issues reveal that he was also a staunch opposer of Cybertron's current government regime but was never able to get his message across because of his peaceful, nobody nature. Then he got pissed, built and attached a fusion cannon to his arm, and the rest was history.
The comics further show that the Decepticons had to come from somewhere, and the corrupt government had many of the Cons coming out of the Lower-classes. Of the Big Three: Soundwave was a vagrant with no memory of his past, Starscream was a test pilot, though it's downplayed with Shockwave who was actually a prominent senator who was Punished for Sympathy and had his emotions stripped from him, becoming the un-empathetic Mad Scientist he is today. All the other cons had mid to low level jobs, Blitzing was a security officer, Needlenose was a salesman, Rumble and Frenzy were miners, though this is inverted with Drag-strip who went from a famous racer to a fairly low-level Decepticon.
One of the biggest examples from Marvel Comics is Galactus, the Devourer of Worlds, who began his life as a simple mortal explorer trying to figure out what was going on as his universe ends around him... after merging with the cosmic egg, he is reborn in the new universe as one of the nigh-omnipotent embodiments of existence, feared throughout the entire universe by every civilization that knows he exists.
Black Hand was a C-list villain (based on Batman co-creator Bill Finger) who stole energy from the Green Lantern and based his persona and crimes off of in-jokes and folk sayings. At one point he gave up supervillainy to run a porno theater. He then led the Black Lanterns, and was a primary antagonist in the DC Crisis Crossover, Blackest Night.
Captain America's Arch-Enemy the Red Skull started his life as a poor starving orphan named Johann Schmidt. Growing up in post WWI Germany as a petty thief, he eventually landed a job as a bellhop in a classy hotel. One day, he was performing his duties as a bellhop when he happened to be in the same room as Hitler himself while the latter was berating an officer. After seeing Schmidt, Hitler exclaimed he could turn the bellhop into a better Nazi than the officer. He did.
Speaking of Nazis, Max Eisenhardt was just a poor boy who had the terrible luck of being born into a Jewish family in Nazi Germany. After a truly tragic Start of Darkness that started in the Death Camps and ended in an America entrenched in racism, Max is no longer a boy but a very angry man who not long ago discovered he possesses incredible powers. He's also assumed a few aliases along the way; the latest one? Erik Magnus Lensherr, a.k.a. Magneto.
In Wanted, Wesley Gibson started out as a weak-willed and pacifistic individual and eventually becoming a monster with his father's Improbable Aiming Skills. This was all masterminded by his father, who hated how Wesley's mother raised him and wanted him to "man up" by embracing his supervillain heritage. Arguably the film version is a less evil variation, where Wesley just becomes a Badass instead.
One memorable twist in Larry Hama's run on the G.I. Joe comic book was revealing that the Cobra Commander was... a used car salesman driven to madness by personal loss and misfortune, who built his terrorist army through propaganda and the proceeds from Amway-style pyramid schemes.
Then there's Lex Luthor, who grew from a kid in Suicide Slum (or Smallville, depending on when you started reading Superman) to supergenius and probably the single richest, most powerful, and corrupt businessman in the entire DC Universe.
Blackest Night reveals that the Entities, the embodiments of Hope, Compassion, Greed, Fear, Willpower, Love, and Rage, were originally the first lifeforms to feel those particular emotions. Parallax, the one responsible for Hal Jordan's Face–Heel Turn which nearly wiped out the universe in Zero Hour... used to be an ordinary little bug.
Which also counts as Fridge Brilliance, as Parallax is the embodiment of Fear; what creature would be more likely to be afraid than an insignificant little bug?
When the Spot returns in Amazing Spider-Man #589, he has been driven insane after being trapped too long in his spotted dimension and starts killing mobsters for shooting his son. He uses his powers in surprisingly ruthless ways, makes Spider-Man punch himself in the face◊, and almost succeeds in killing a Russian mob boss. He only fails because Spidey talks him out of it.
The Jackal: Biology professor who fancied Gwen Stacy.
Green Goblin: There have been three villains with this name - an inventor and businessman, a college student, and a psychiatrist. The third, however, did prove to be ineffectual.
The first Hobgoblin, a villain modeled after the Green Goblin, was a fashion designer. For a while, he had a mild-mannered reporter brainwashed to pose as the Hobgoblin as well. This trope was averted with the second Hobgoblin, however, who was a previous mercenary and supervillain Jack O' Lantern.
The ultimate Big Bad of the CrossGen multiverse, Charon of the Negation Universe, was an ordinary archaeologist who had the good(bad?) luck of discovering Atlantis and its Ascension technology. When his comrade Apollyon activated it, they were both flung into the Negation Universe as partially ascended near omnipotent godlike beings. Charon became so powerful that the mere fragments of his madness which he expelled from himself became twisted Eldritch Abominations called the Lawbringers that are powerful enough to fight and killThe First and Sigil-Bearers.
In his first appearance in Captain Britain, Mad Jim Jaspers was a gimmicky Harmless Villain who ended up effortlessly trounced by the Captain and completely forgotten about. A few issues later, he reappears and unleashes his reality-warping powers, conquering first Earth and then the entire universe, bending it to his twisted will and reducing its inhabitants to utter insanity. And Captain Britain is powerless to stop him.
The Human Flame from The DCU is a subversion. True, he started out a pathetic D-list villain that gained incredible power during his mini. The subversion is that, even with a huge power boost, he's still pathetic.
Abraham Pointe was a creepy nobody photographer stalking a waitress in a Las Vegas casino. Then he got possessed by the Predator, the Entity of Love, and became a superpowered stalker.
Eli Bard from X-Force went from a soldier to a respected Roman senator - until his wife stabbed him in the back. After that he went from a destitute ex-senator to vampiric monstrosity who not only commits mass murder but manages to overpower some other genuinely badass individuals.
Scourge The Hedgehog from Archie Comics' Sonic the Hedgehog is most definitely this. In his own words, he was an evil alternate dimension counterpart of Sonic, who was nothing but a minor annoyance. It was only when he became super-charged with energy from the Master Emerald that he became a monster - to the point where he actually took over his home planet just because he could. It's also implied that he's a Self-Made Orphan.
Doctor Finitevus. Ordinarily a brilliant mind from the Echidna city of Albion, an incident involving Chaos Knuckles, Saffron and Charmy Bee, and an invention of his own creation led to his transformation into one of the worst villains Mobius had ever seen. Dangerous and manipulative, he nearly brought about The End of the World as We Know It by using Knuckles, and was directly responsible for Albion's destruction and the deaths of hundreds of Echidnas.
Chaos started out as a Drakon Prosecutor from ancient times, during the war between the echidnas and the Drakon Empire capture by echidnas not long after its imprisonment, a squad of Drakons attacked the camp in order to take back the Chaos Emeralds that the echidnas had stolen from them. During the fight, a discharge from a Prosecutor's battle-staff struck the Chaos Emeralds, causing the Emeralds to 'leak' pure Chaos radiation. The energy mingled with the water in the tank containing the captive Prosecutor, which absorbed the energy and was mutated in a terrifying monstrosity, the creature Sonic would come to know in the future as Chaos.
The Cirinist from Cerebus were originally a group of mothers who worked together to help their community. Over the course of the first 1/3 of the series they go from a creepy Monster of the Week to a major political party to an oppressive matriarchy and eventually the closest thing to a Big Bad the series has.
New Joanne was originally a writer for a religious magazine but by the end of the series she runs the oppressive matriarchy that rules the world and is arguably worst than the Cirinists.
Vandal Savage was just an ordinary caveman before he found the meteor that gave him his powers. Had he not, he would have certainly died with no one ever remembering him. Instead he became one of the vilest, cruelest villains in the DC Universe, a man responsible for untold murders and multiple wars, and was the first cannibal. All because he was attracted to a bright light...
Ultron started out as Hank Pym just tinkering around in his lab. Flashbacks revealed his original appearance looked about as threatening as WALL-E. Then he rebuilt himself a skull face and glowing red eyes...
In at least one alternate future, Victor Mancha of the Runaways is destined to become Victorious, a dreaded, mass-murdering super-villain who slaughters the Avengers. But in the present, he's pretty much the designated Butt Monkey of his team.
The Runaways' original enemies, The Pride, were all a bunch of nobodies and small-time crooks, until they were summoned by a trio of monstrous descendants of fallen angels who offered them work. Since then they have been a criminal organization that controlled underground activities on the West Coast yet managed to stay undercover in the Marvel Universe for years, were respected by such powerhouses of crime as the Kingpin or the Hellfire Club, and at one point gave the Marvel Illuminati — a group composed of Iron Man, Reed Richards, Black Bolt, Doctor Strange, Charles Xavier and Namor the Sub-Mariner — a run for their money.
Parker Robbins was a loser and small-time crook, until he stole a magic cloak and boots. As The Hood, he quickly rose in rank in the criminal world, until turning into the leader of a gang strong enough to butt heads with The Avengers and live to tell the tale, gaining himself a place in the Cabal.
At one point other supervillains wonder why exactly they follow him and his cousin calls this trope - they all started as nobodies before becoming superpowered crooks, but they had normal lives, while Parker was the only one to start from the bottom and knew what to do to crawl his way to the top.
Unfortunately, this ultimately got Robbins addicted to power for its own sake. When he lost the cloak and boots, he desperately scrambled for new super powers since he can't bear going back to being a nobody.
Transformers: Wings of Honor: Inverted: Before the war, Strika was a security guard assigned to a scientific outpost, at the end of the Autobot-Decepticon war she's one of the Autobot's top Generals and Co-leads the Autobot/Decepticon alliance against the Cybertronian empire.
The Secret Service shows Gary's transition from a random street punk to a world class spy.
Coach Boss from Southern Bastards was a skinny kid who repeatedly failed to get in the football team. He goes on to become the crime boss of the entire town.
While not a villain in the proper sense, Lenore the Cute Little Dead Girl from the eponymous comic series is pretty horrifying at times. She was apparently a mostly normal child before catching pneumonia, dying, and rising from the dead as an adorable little abomination.
Gorr the God Butcher from The Mighty Thor used to be a poor starving mortal. After acquiring All Black the Necrosword, he became a god-killing abomination who singlehandedly wiped out entire pantheons across the cosmos.
Reed Richards from Ultimate Fantastic Four started out as a bullied teenager mocked for his intelligence, became a superhero, but after growing out of favor with the way the world is run, decided to take over the world, and now he's basically the Ultimate version of Kang the Conqueror.
Johnny Sorrow was a silent movie star whose career was ruined by the coming of talkies. Turning to crime, he used a device to become intangible until a battle with the JSA caused it to malfunction and suck him into another dimension. There, he was transformed into a twisted being whose face literally kills anyone who gazes upon it and determined to make Earth pay for his condition.
Maxwell Lord was your typical yuppie, ruthless in the field, even wiling to let his boss die to get ahead but trying to save him. He seemed a good guy working with the Justice League and gaining the power to push his will on others. But when Cyborg Superman destroyed Coast City (where his mother lived), Max became convinced that metahumans caused more problems than they solved. Driven by his new crusade Max would become more obsessed with "saving" humanity...which ended up turning him into a mass murdering menace.